MAMMARY CARCINOGENESIS--THE ROLE OF PLEIOTROPHIN

  • Lupu, Ruth (PI)
  • Kern, Francis (PI)
  • Soonmyoung, Pai (PI)
  • Byers, Stephen (PI)
  • Ziff, Barbara (PI)
  • Mazumder, Amitabha (PI)
  • Russell, Kathy (PI)
  • Trock, Bruce (PI)
  • Wellstein, Anton (PI)
  • Clarke, Robert (PI)
  • Honig, Susan (PI)
  • Dickson, Robert B. (PI)
  • Ziff, Barbara (PI)
  • Trock, Bruce (PI)
  • Swain, Sandra (PI)
  • Honig, Susan Flamm (PI)
  • Delap, Robert (PI)
  • Lippman, Marc (PI)
  • Soonmyoung, Pai (PI)
  • Byers, Stephen (PI)
  • Mazumder, Amitabha (PI)
  • Russell, Kathy (PI)
  • Wellstein, Anton (PI)
  • Clarke, Robert (PI)
  • Dickson, Robert B. (PI)

Project: Research project

Project Details

Description

Mammary Carcinogenesis: The Role of Pleiotrophin. Breast cancer growth
and metastasis requires growth factor signals between the tumor cells and
the normal surrounding host tissue. We propose that the secreted
polypeptide growth factor pleiotrophin (PTN) plays a major role in
mammary carcinogenesis as well as in the growth and metastasis of breast
cancer. This hypothesis is based on the biological effects of PTN
expression in selected tumors models, the high levels of PTN mRNA in 60%
of tumor samples from breast cancer patients and on its upregulation
during carcinogen-induced rodent mammary cancer. Furthermore, PTN is
highly expressed in immature mouse mammary glands that are sensitive to
carcinogens and is downregulated permanently in mice that have undergone
pregnancy and are protected against carcinogenesis. Finally, the activity
of PTN on endothelial cells in vitro suggests that PTN can serve as an
angiogenesis factor during tumor progression. In support of this role of
PTN as an angiogenesis factor, reduction of constitutively expressed
endogenous rib mRNA in human tumor cell lines by PTN-targeted ribozymes
reduced tumor growth and metastasis even when in vitro growth of the
tumor cells remained unaffected.

Based on these preliminary studies, we wish to elucidate the role of PTN
in breast cancer progression and in mammary carcinogenesis with the
ultimate goal to develop better prognostic markers as well as novel
therapeutic strategies.

Under aim 1 we will study whether serum levels of PTN in breast cancer
patients can predict long term outcome of their disease an-or the
response to therapy. We will use samples from patients with over 10 years
of follow-up from our serum bank core facility for this analysis. Under
aim 2 we will study to what extent hormonal regulation affects PTN
expression in mammary gland maturation and during mammary carcinogenesis
in rodent models. We will study the influence of steroid hormones and
retinoid acid receptor ligands on PTN expression and on mammary gland
biology or carcinogenesis in animals and in organ culture. Under aim 3
we will study to what extent sustained high levels of expression of rib
will affect mammary gland maturation, hormonal responsiveness and
susceptibility to carcinogens at different stages of mammary gland
maturation. To achieve this, we will express PTN as a transgene in mice
under a tetracycline-regulated promoter. We will study the effects of a
challenge of the transgenic animals (and of organ explants) with hormonal
stimuli as well as with carcinogens. Under aim 4 we will study to what
extent reduction of endogenous PTN expression will affect mammary gland
physiology and pathology. We will use ribozyme-targeting of rib to
achieve this goal. We will generate mice expressing PTN-targeted
ribozymes under the control of a tetracycline-regulated promoter and
study spontaneous gland maturation during pregnancy as well as the
effects of hormonal and carcinogen challenges with the endogenous PTN
suppressed by the ribozyme transgene. Under aim 5 we will develop gene
transfer vectors to target rib expression with ribozymes in vivo. We will
use adenovirus- and herpes virus-based vectors for gene transfer.
StatusFinished
Effective start/end date9/30/928/31/05

Funding

  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

ASJC

  • Medicine(all)

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